Substituted 3-(aminoalkylamino)-1,2-benzisoxazoles and related compounds

ABSTRACT

This application relates to compounds of the formula ##STR1## wherein R 1 , X, Y and n are as defined in the specification; and pharmaceutically acceptable addition salts thereof and optical and geometric isomers or racemic mixtures thereof; which compounds are useful for the treatment of various memory dysfunctions characterized by a decreased cholinergic function such as Alzheimer&#39;s disease. Compounds of this invention also inhibit monoamine oxidase and hence are useful as antidepressants.

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 980,021, filed Nov. 23, 1992, now abandoned.

This application relates to compounds of the formula ##STR2## wherein

R¹ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonyl, aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl,aminocarbonyl, (C₁ -C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl;

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, amino, (C₁-C₆)alkylamino, di(C₁ -C₆)alkylamino, aryl(C₁ -C₆)alkylamino, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy,aryl(C₁ -C₁₀)alkylaminocarbonyloxy, (C₁ -C₆)alkoxycarbonyloxy, aryl(C₁-C₆)alkylcarbonyloxy;

Y is oxygen (O), sulfur (S) or NR¹⁰ where R¹⁰ is hydrogen, (C₁-C₆)alkyl, aryl or aryl(C₁ -C₆)alkyl;

R² is ##STR3## or R¹ and R² together with the nitrogen to which they areattached form the ring ##STR4## where

R³ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁ -C₆)alkylcarbonyl,(C₁ -C₆)alkoxycarbonyl, (C₃ -C₆)alkenyl, (C₃ -C₆)alkynyl, aryl, amino(C₁-C₆)alkyl, mono(C₁ -C₆)alkylamino(C₁ -C₆)alkyl or di(C₁-C₆)alkylamino(C₁ -C₆)alkyl;

R⁴ is hydrogen or (C₁ -C₆)alkyl;

R⁵ is hydrogen, hydroxy, (C₁ -C₆)alkoxy, amino(C₁ -C₆)alkyl, monoaryl(C₁-C₆)alkylamino(C₁ -C₆)alkyl, diaryl(C₁ -C₆)alkylamino(C₁ -C₆)alkyl, (C₁-C₆)alkanoyloxy or aryl(C₁ -C₆)alkyl;

R⁶ is hydrogen, (C₁ -C₆)alkyl, aryl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkylcarbonyl, aryl(C₁ -C₆)alkylcarbonyl or (C₁ -C₆)alkoxycarbonyl;

R⁷ is hydrogen, (C₁ -C₆)alkyl, (C₂ -C₆)alkenyl, (C₃ -C₆)alkynyl, phenyl,aryl(C₁ -C₆)alkyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl orquinolinyl;

R⁸ and R⁹ are independently hydrogen, (C₁ -C₆)alkyl or aryl(C₁-C₆)alkyl;

R¹¹ is (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, halogen, nitro ortrifluoromethyl;

m is an integer from 2 to 7;

n is an integer from 0 to 3;

p is an integer from 1 to 3;

r is an integer from 0 to 2; and

s is an integer from 0 to 6;

and pharmaceutically acceptable addition salts thereof and optical andgeometric isomers or racemic mixtures thereof; which compounds areuseful for the treatment of various memory dysfunctions characterized bya decreased cholinergic function such as Alzheimer's disease. Compoundsof this invention also inhibit monoamine oxidase and hence are useful asantidepressants.

Unless otherwise stated or indicated, the following definitions shallapply through the specification and the appended claims.

The term (C₁ -C₆)alkyl or (C₁ -C₁₀)alkyl shall mean a straight orbranched alkyl group, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, t-butyl and straight and branched chainpentyl, hexyl, heptyl and decyl.

The term halo shall mean fluorine, chlorine, bromine or iodine.

The terms phenyl, pyrimidyl, pyridazinyl, pyrazinyl and quinolinyl shallmean the respective group substituted with 0, 1 or 2 substituents eachof which being independently (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy,halogen, nitro or trifluoromethyl.

The term pyridyl shall mean a 2-pyridyl, 3-pyridyl or 4-pyridyl groupsubstituted with 0, 1 or 2 substituents each of which beingindependently (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, halogen, nitro ortrifluoromethyl.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, optical, enantiomeric andtautomeric isomers where such isomers exists.

In one class of compounds of this invention are compounds of the formula##STR5## wherein X, R¹, n and m are as defined above and Z is ##STR6##where

R³ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁ -C₆)alkylcarbonyl,(C₁ -C₆)alkoxycarbonyl, (C₃ -C₆)alkenyl, (C₃ -C₆)alkynyl or aryl;

R⁴ is hydrogen or (C₁ -C₆)alkyl;

R⁵ is hydrogen, hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkanoyloxy or aryl(C₁-C₆)alkyl;

R⁶ is hydrogen, (C₁ -C₆)alkyl, aryl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkylcarbonyl. aryl(C₁ -C₆)alkylcarbonyl or (C₁ -C₆)alkoxycarbonyl;

R¹¹ is (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, halogen, nitro ortrifluoro;

m is an integer from 2 to 7;

n is an integer from 0 to 3; and

r is an integer from 0 to 2.

In one preferred embodiment of this class are compounds of the formula##STR7## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonyl, aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl,aminocarbonyl, (C₁ -C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl;

m is an integer from 2 to 7;

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹ is hydrogen or (C₁ -C₆)alkyl;

n is 1 or 2; and

m is 2, 3 or 4.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy;

R¹ is hydrogen or methyl; and

m is 2.

In another preferred embodiment of this class are compounds of theformula ##STR8## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonyl, aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl,aminocarbonyl, (C₁ -C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl;

m is an integer from 2 to 7;

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, (C₁ -C₈)alkylaminocarbonyloxy,tetrahydroisoquinolylcarbonyloxy, di(C₁ -C₈)alkylaminocarbonyloxy oraryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹ is hydrogen or (C₁ -C₆)alkyl;

n is 1 or 2; and

m is 2, 3 or 4.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 6-methoxymethoxy, 5-phenylmethylaminocarbonyloxy, 6-hydroxy,6-methoxy, 6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy;

R¹ is hydrogen or methyl; and

m is 2.

In yet another preferred embodiment of this class are compounds of theformula ##STR9## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonyl, aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl,aminocarbonyl, (C₁ -C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl;

R⁶ is hydrogen, (C₁ -C₆)alkyl, aryl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkylcarbonyl, aryl(C₁ -C₆)alkylcarbonyl or (C₁ -C₆)alkoxycarbonyl;

m is an integer from 2 to 7;

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, di(C₁ -C₈)alkylaminocarbonyloxy,tetrahydroisoquinolylcarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹ is hydrogen or (C₁ -C₆)alkyl;

R⁶ is (C₁ -C₆)alkyl or aryl(C₁ -C₆)alkyl;

n is 1 or 2; and

m is 2, 3 or 4.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-dimethylaminocarbonyloxy, 5-heptylaminocarbonyloxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-phenylmethylaminocarbonyloxy, 5-hexylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy;

R¹ is hydrogen or methyl;

R⁶ is phenylmethyl; and

m is 2.

In another preferred embodiment of this class are compounds of theformula ##STR10## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonyl, aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl,aminocarbonyl, (C₁ -C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl;

R¹¹ is (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, halogen, nitro ortrifluoro;

m is an integer from 2 to 7;

n is an integer from 0 to 3;

r is an integer from 0 to 2; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹ is hydrogen or (C₁ -C₆)alkyl;

n is 1 or 2; and

m is 2, 3 or 4.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy;

R¹ is hydrogen or methyl; and

m is 2.

In yet another embodiment of this class are compounds of the formula##STR11## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkyloxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonyl, aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl,aminocarbonyl, (C₁ -C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl;

R⁶ is hydrogen, (C₁ -C₆)alkyl, aryl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkylcarbonyl, aryl(C₁ -C₆)alkylcarbonyl or (C₁ -C₆)alkoxycarbonyl;

m is an integer from 2 to 7;

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹ is hydrogen or (C₁ -C₆)alkyl;

R⁶ is aryl(C₁ -C₆)alkyl;

n is 1 or 2; and

m is 2, 3 or 4.

Preferably in this embodiment

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy;

R¹ is hydrogen or methyl;

R₆ is phenylmethyl; and

m is 2.

In another embodiment of this class are compounds of the formula##STR12## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonyl, aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl,aminocarbonyl, (C₁ -C₆)alkylaminocarbonyl, or di(C₁-C₆)alkylaminocarbonyl;

R³ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁ -C₆)alkylcarbonyl,(C₁ -C₆)alkoxycarbonyl, (C₃ -C₆)alkenyl, (C₃ -C₆)alkynoyl, aryl,amino(C₁ -C₆)alkyl, mono(C₁ -C₆)alkylamino, (C₁ -C₆)alkyl or di(C₁-C₆)alkylamino(C₁ -C₆)alkyl;

R⁴ is hydrogen or (C₁ -C₆)alkyl;

m is an integer from 2 to 7;

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹ is hydrogen or (C₁ -C₆)alkyl;

R³ is (C₁ -C₆)alkyl;

R⁴ is hydrogen;

n is 1 or 2; and

m is 2, 3 or 4.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy;

R¹ is hydrogen or methyl;

R³ is methyl;

R⁴ is hydrogen; and

m is 2.

In another class of compounds of this invention are compounds of theformula ##STR13## wherein

X is as defined above; and

U is N--R⁷, (CH₂)_(s) amino where the amino group is unsubstituted ormono or disubstituted with (C₁ -C₆)alkyl or aryl(C₁ -C₆)alkyl; and s isan integer from 1 to 6; and

R⁷ is hydrogen, (C₁ -C₆)alkyl, phenyl, phenyl(C₁ -C₆)alkyl, (C₂-C₆)alkenyl, (C₃ -C₆)alkynyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinylor quinolinyl.

In one preferred embodiment of this class are compounds of the formula##STR14## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy; and

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy; and

n is 1 or2.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy.

In yet another embodiment are compounds of the formula ##STR15## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy or di(C₁-C₈)alkylaminocarbonyloxy, aryl(C₁ -C₆)alkylaminocarbonyloxy; and

n is 1 or2.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy.

In another embodiment of this class are compounds of the formula##STR16## wherein X and R⁷ are as defined above.

In a preferred embodiment of this class are compounds of the formula##STR17## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, or tetrahydroisoquinolylcarbonyloxy oraryl(C₁ -C₆)alkylcarbonyloxy;

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof;

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy or di(C₁-C₈)alkylaminocarbonyloxy, aryl(C₁ -C₆)alkylaminocarbonyloxy; and

n is 1 or2.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy.

In one preferred embodiment of this class are compounds of the formula##STR18## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy; and

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy; and

n is 1 or 2.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy.

In yet another embodiment are compounds of the formula ##STR19## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy; and

n is an integer from 0 to 3; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy; and

n is 1 or 2.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy.

In one preferred embodiment of this class are compounds of the formula##STR20## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, or tetrahydroisoquinolylcarbonyloxy oraryl(C₁ -C₆)alkylcarbonyloxy;

R¹¹ is (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, halogen, nitro ortrifluoromethyl;

n is an integer from 0 to 3;

r is an integer from 0 to 2; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹¹ is (C₁ -C₆)alkyl or halogen;

n is 1 or 2; and

r is 0 or 1.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy.

R¹¹ is methyl; and

r is 0 or 1.

In yet another embodiment are compounds of the formula ##STR21## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹¹ is halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, nitro ortrifluoromethyl;

n is an integer from 0 to 3;

r is an integer from 0 to 2; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy or di(C₁-C₈)alkylaminocarbonyloxy, aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹¹ is (C₁ -C₆)alkyl or halo;

n is 1 or 2; and

r is 0 or 1.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy; and

R¹¹ is 4-chloro.

In another embodiment are compounds of the formula ##STR22## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹¹ is halogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, nitro ortrifluoromethyl;

n is an integer from 0 to 3;

r is an integer from 0 to 2; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹¹ is halogen or (C₁ -C₆)alkyl;

n is 1 or 2; and

r is 0 or 1.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy; and

R¹¹ is 5-chloro.

In another embodiment of this class are compounds of the formula##STR23## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹¹ is halogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, nitro ortrifluoromethyl;

n is an integer from 0 to 3;

r is an integer from 0 to 2; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

R¹¹ is halo or (C₁ -C₆)alkyl;

n is 1 or 2; and

r is 0 or 1.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy; and

R¹¹ is 5-chloro.

In another embodiment are compounds of the formula ##STR24## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹¹ is halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, nitro ortrifluoromethyl;

n is an integer from 0 to 3;

r is an integer from 0 to 2; and

pharmaceutically acceptable acid addition salts thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

n is 1 or 2; and

r is 0 or 1.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-isopropylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy; and

r is 0 or 1; and

R¹¹ is methyl.

In yet another embodiment are compounds of the formula ##STR25## wherein

X is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo, hydroxy, (C₁-C₆)alkanoylamino, aminocarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy,di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁ -C₁₀)alkylaminocarbonyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydroisoquinolylcarbonyloxy or aryl(C₁-C₆)alkylcarbonyloxy;

R¹¹ is halogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, hydroxy, nitro ortrifluoromethyl;

n is an integer from 0 to 3;

r is an integer from 0 to 2; and

pharmaceutically acceptable acid addition sails thereof and optical andgeometric isomers or racemic mixtures thereof.

Preferably in this embodiment

X is hydrogen, hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy;

n is 1 or 2; and

p is 0 or 1.

Most preferably

X is hydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethyaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 5-phenylmethylaminocarbonyloxy, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy; and

R¹¹ is hydrogen, trifluoromethyl or chloro.

Nonlimiting examples of compounds of this invention include:

6-Methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

3-[[2-(4-Morpholinyl)-ethyl]methylaminol-1,2-benzisoxazol-6-ol;

3-[[2-(4-Morpholinyl)-ethyl]methylamino]-1,2-benzisoxazol-6-ylmethylcarbamate;

3-[[2-(4-Morpholin-yl)ethyl]methylamino]-1,2-benzisoxazol-6-ylphenylmethyl carbamate;

3-[[2-(4-Morpholinyl)-ethyl]methylaminol-1,2-benzisoxazol-6-yl1-methylethyl-carbamate;

N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

N-[2-(4-Morpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

6-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

3-[[2-(4-Morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol;

3-[[2-(4-Morpholinyl)-ethyl]methylaminol-1,2-benzisoxazol-5-ol;

3-[[2-(4-Morpholinyl)-ethyl]amino]-1,2-benzisoxazol-6-ylmethylcarbamate;

3-[[2-(4-Morpholinyl)ethyl]amino]-1,2-benzisoxazol-5-yl methylcarbamate;

6-Chloro-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

1-Methyl-N-[2-(4-morpholinyl)ethyl]-1,2-indazol-3-amine;

N-Methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisothiazol-3-amine;

5-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazole-3-amine;

7-Bromo-6-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

5-Bromo-6-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

3-[[2-(4-Morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-yldimethylcarbamate;

3-[[(Methylamino)carbonyl][2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazolo-6-ylmethylcarbamate;

3-[[(Methylamino)carbonyl][2-(4-morpholinyl)ethyl]-amino]-1,2-benzisoxazol-5-ylmethylcarbamate;

6-Methoxymethoxy-N-[2-(4-thiomorpholinyl)ethyl]-1,2-benzisoxazol-3-amine;

3-[[2-(4-Thiomorpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol;

6-Methoxy-N-methyl-N-[2-[4-(1-phenylmethyl)piperdinyl]-1,2-benzisoxazol-3-amine;

7-Bromo-3-[N-methyl,N-2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-6-ol; and

7-Bromo-3-[N-methyl,N-2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-6-yldimethylcarbamate.

The compounds of the invention are prepared by one or more of thesynthetic routes described below.

Throughout the description of the synthetic schemes, the notations X,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and Y have the respectivemeanings given unless otherwise stated or indicated and other notationshave the respective meanings defined in their first appearances.

More particularly, as shown in Reaction Scheme A, the chloro compound ofFormula III is reacted with an amino compound of Formula IV to yield thecompound of Formula V. The reaction is typically carded out neat in asealed tube at a temperature of from about 100° C. to about 200° C.,preferably from about 120° C. to about 180° C., most preferably fromabout 130° C. to about 150° C. for from about 1.0 hour to about 100hours, preferably from about 12 hours to about 72 hours, most preferablyfrom about 30 hours to about 60 hours.

When X is alkoxy the compound of Formula V can be treated with acid suchas, for example, 48% hydrobromic acid, to yield the correspondinghydroxy compound of Formula VI. The reaction is typically carried out atreflux for from about 1 hour to about 12 hours, preferably from about 2hours to about 4 hours.

The hydroxy compound of Formula VI is treated with the appropriateisocyanate, carbamoylchloride or carbonyldiimidazole and an amine toobtain the compound of Formula VII wherein R⁷ is (C₁ -C₁₀)alkyl oraryl(C₁ -C₁₀)alkyl. The reaction is carried in an inert organic solventsuch as for example ethyl acetate for about 0.5 hours to about 24 hours,optionally in the presence of a catalyst such as for examplecopper(I)chloride.

Additionally, the hydroxy compound of Formula VI can be treated with analkyl, aryl or aralkylhalide, such as for example a benzyl halide, underbasic conditions as known in the art to yield the corresponding alkoxy,aryloxy or arylalkoxy compounds of Formula V. ##STR26##

Alternatively, the compounds wherein R¹ is hydrogen are synthesized asshown in Reaction Scheme B wherein the amino compound of Formula VIII isreacted with the halo, preferably chloro, compound of Formula IX toobtain the compound of Formula X. The reaction is typically carried outin a polar inert solvent such as dimethylformamide (DMF). The aminocompound of Formula VIII is first converted to its corresponding salt,such as, for example, its sodium salt, by reaction with sodium hydrideat ambient temperature for about 1 hour. The salt is subsequentlyreacted without isolation with the halo compound at from about ambienttemperature to about 150° C., preferably from about 100° C. to about130° C. for about 1 hour.

In the case where X is alkoxy, the compound of Formula X is converted tothe corresponding hydroxy compound of Formula XI essentially asdescribed for the compound of Formula VI. Subsequent treatment with anisocyanate yields both the monosubstituted compound of Formula XII andthe disubstituted compound of Formula XIII. The mixture of the compoundsof Formula XII and XIII can be separated by means known in the art, forexample, chromatographically. ##STR27##

In the case where R₁ and R₂ together form a ring, the chloro compound ofFormula III when X is alkoxy is reacted with the cyclic amino compoundof Formula XVI or XVII to yield the compound of Formula XVIII or XVIXrespectively as shown in Reaction Scheme C. The reaction is typicallycarried out neat in a sealed tube at a temperature of from about 100° C.to about 200° C., preferably from about 120° C. to about 180° C., mostpreferably from about 130° C. to about 150° C. for from about 1.0 hourto about 100 hours, preferably from about 1 hour to about 72 hours, mostpreferably from about 2 hours to about 48 hours.

In the case where R⁷ is hydrogen, the compound of Formula XVIII can thenbe reacted with the appropriate halo compound, optionally in thepresence of a base such as triethylamine or sodium bicarbonate to obtainthe desired compounds where R⁷, R⁸ and R⁹ is not hydrogen. The reactionis typically carried out either reactor in an organic solvent such asfor example methylene chloride, dimethylformamide or ethanol.Alternatively, R⁷, R⁸ and R⁹ can be other than hydrogen in the firststep depicted in this reaction scheme.

The alkoxy compounds are then reacted as shown in Reaction Scheme A.##STR28##

In the case where X is amino or substituted amino the compounds can beprepared from the corresponding nitro compound which is reduced, byknown means, for example, by catalytic reduction. The amino compound issubsequently acylated by means known in the art to provide the amidecompounds of the invention. The nitro compounds can be prepared eitherby nitration of the compound of Formula III or by means known in theart.

The starting compounds of Formula III are prepared by means known in theart, for example Yevich, J. P. el. al., J. Med Chem., 29, 359-69 (1986).

The starting compounds of Formula VIII are prepared from thecorresponding orthofluorobenzonitriles or orthonitrobenzonitriles asshown in Reaction Scheme D.

More particularly the benzonitrile of Formula XIV where Q is fluoro ornitro and X is as stated above or nitro is reacted with acetohydroxamicacid in an inert polar solvent such as, for example DMF in the presenceof a base such as, for example, potassium tertiary butoxide, to obtainthe amino compound of Formula VIII directly. Alternatively, thebenzonitrile of Formula XIV is reacted with acetone oxime in thepresence of a base such as, for example, sodium hydride, to yield thecorresponding methylethylideneaminoxybenzonitrile of Formula XV. Thecompound of Formula XV is subsequently cyclized to the correspondingamino compound of Formula VIII by treatment with acid such as, forexample, hydrochloric acid. ##STR29##

The starting compounds of Formula III or VII where X is alkoxy arebrominated by means known in the art to obtain the correspondingbrominated compound.

More particularly, as shown in Reaction Scheme E, the compound ofFormula III is brominated in an acid such as for example, acetic acid,at about ambient temperature and the compound of Formula XVI isbrominated in a solvent such as for example, methanol at lowtemperatures, preferably, at about -50° C. ##STR30##

The compounds of the present invention are useful for the treatment ofvarious memory dysfunctions characterized by a decreased cholinergicfunction such as Alzheimer's disease. Compounds of this invention alsoinhibit monoamine oxidase and hence are useful as antidepressants.

Cholinesterase Inhibition Assay

Cholinesterases are found throughout the body, both in the brain and inserum. However, only brain acetylcholinesterase (AChE) distribution iscorrelated with central cholinergic innervation. This same innervationis suggested to be weakened in Alzheimer patients. We have determined invitro inhibition of acetylcholinesterase activity in rat striatum.

In Vitro Inhibition of Acetylcholinesterase Activity in Rat Striatum

Acetylcholinesterase (AChE), which is sometimes called true or specificcholinesterase, is found in nerve cells, skeletal muscle, smooth muscle,various glands and red blood cells. AChE may be distinguished from othercholinesterases by substrate and inhibitor specificities and by regionaldistribution. Its distribution in brain roughly correlates withcholinergic innervation and subfractionation shows the highest level innerve terminals.

It is generally accepted that the physiological role of AChE is therapid hydrolysis and inactivation of acetylcholine. Inhibitors of AChEshow marked cholinomimetic effects in cholinergically-innervatedeffector organs and have been used therapeutically in the treatment ofglaucoma, myasthenia gravis and paralytic ileus. However, recent studieshave suggested that AChE inhibitors may also be beneficial in thetreatment of Alzheimer's disease.

The method described below was used in this invention for assayingcholinesterase activity. This is a modification of the method of Ellmanet al., Biochem. Pharmacol. 7, 88 (1961).

Procedure:

A. Reagents--

1. 0.05M Phosphate buffer, pH 7.2

(a) 6.85 g NaH₂ PO₄.H₂ O/100 ml distilled H₂ O

(b) 13.40 g Na₂ HPO₄.7H₂ O/100 ml distilled H₂ O

(c) add (a) to (b) until pH reaches 7.2

(d) Dilute 1:10

2. Substrate in buffer

(a) 198 mg acetylthiocholine chloride (10 mM)

(b) bring to 100 ml with 0.05M phosphate buffer, pH 7.2 (reagent 1)

3. DTNB in buffer

(a) 19.8 mg 5,5-dithiobisnitrobenzoic acid (DTNB) (0.5 mM)

(b) bring to 100 ml with 0.05M phosphate buffer, pH 7.2 (reagent 1)

4.. A 2 mM stock solution of the test drug is made up in a suitablesolvent and brought to volume with 0.5 mM DTNB (reagent 3).

Drugs are serially diluted (1:10) such that the final concentration (incuvette) is 10⁻⁴ M and screened for activity. If active, IC₅₀ values aredetermined from the inhibitory activity of subsequent concentrations.

B. Tissue Preparation--

Male Wistar rats are decapitated, brains rapidly removed, corporastriata dissected free, weighed and homogenized in 19 volumes(approximately 7 mg protein/ml) of 0.05M phosphate buffer, pH 7.2 usinga Potter-Elvehjem homogenizer. A 25 microliter aliquot of the homogenateis added to 1.0 milliter vehicle or various concentrations of the testdrug and preincubated for 10 minutes at 37° C.

C. Assay--

Enzyme activity is measured with the Beckman DU-50 spectrophotometer.This method can be used for IC₅₀ determinations and for measuringkinetic constants.

Instrument Settings

Kinetics Soft-Pac Module #598273 (10)

Program #6 Kindata:

Source--Vis

Wavelength--412 nm

Sipper--none

Cuvettes--2 ml cuvettes using auto 6-sampler

Blank--1 for each substrate concentration

Interval time--15 seconds (15 or 30 seconds for kinetics)

Total time--5 minutes (5 or 10 minutes for kinetics)

Plot--yes

Span--autoscale

Slope--increasing

Results--yes (gives slope)

Factor--1

Reagents are added to the blank and sample cuvettes as follows:

    ______________________________________    Blank:   0.8 ml Phosphate Buffer/DTNB             0.8 ml Buffer/Substrate    Control: 0.8 ml Phosphate Buffer/DTNB/Enzyme             0.8 ml Phosphate Buffer/Substrate    Drug:    0.8 ml Phosphate Buffer/DTNB/Drug/Enzyme             0.8 ml Phosphate Buffer/Substrate    ______________________________________

Blank values are determined for each run to control for non-enzymatichydrolysis of substrate and these values are automatically subtracted bythe kindata program available on kinetics soft-pac module. This programalso calculates the rate of absorbance change for each cuvette.

For IC₅₀ Determinations:

Substrate concentration is 10 mM diluted 1:2 in assay yielding finalconcentration of 5 mM. DTNB concentration is 0.5 mM yielding 0.25 mMfinal concentration. ##EQU1##

Results of this assay for some of the compounds of this invention andphysostigmine (reference compound) are presented in Table 1.

                  TABLE I    ______________________________________                          Inhibitory                          Concentration,                          IC.sub.50 (μM)                          Brain AChE    ______________________________________    Compound    3-[N-methyl, N-2-(4-morpholinyl)ethyl]                            13    amino-1,2-benzisoxazol-6-yl    methyl carbamate    7-Bromo-3-[N-methyl, N-2-(4-morpholinyl)-                            2.0    ethyl]amino-1,2-benzisoxazole-6-yl    dimethylcarbamate    6-Methoxy-N-methyl-N-[2-[4-(1-                            4.0    phenylmethyl)piperdinyl]ethyl]-    1,2-benzisoxazol-3-amine sesquihydrochloride    3-[1-(4-Pyridyl)piperazinyl]-1,2-                            0.88    benzisoxazol-6-yl dimethylcarbamate    7-Bromo-6-methoxy-3-[1-(4-pyridyl)-                            14    piperazinyl]-1,2-benzisoxazole    (Reference Compound)    Physostigmine           0.034    ______________________________________

The utility is further demonstrated by the ability of these compounds toinhibit the enzyme monoamine oxidase, increase the brain levels ofbiogenic amine(s), and act as antidepressants.

Inhibition of Type A and Type B Monoamine Oxidase Activity in Rat BrainSynaptosomes

Purpose:

To determine the selective inhibition of the two forms of monoamineoxidase (MAP).

Introduction:

The metabolic deamination of amines has been known for over a hundredyears, but more recently Johnston 1) described two forms of monoamineoxidase, which are called "type A" and "type B". The existence of thetwo forms is based on different substrate and inhbitor specificities.Serotonin (5HT) and norepinephrine (NE) are substrates for type A MAO,β-phenethylamine (PEA) and benzylamine are substrates for type B MAO),while dopamine (DA) and tyramine are substrates for both types.Clorgyline is a selective inhibitor of the type A enzyme, deprenyl andpargyline are selective inhibitors of the type B enzyme andtranylcypromine and iproniazid are nonselective inhibitors (2). It isrecognized that MAO inhibitors have antidepressant properties.

Although various methods for measuring MAO activity are available, thedescribed method involves the extraction of the radiolabeled deaminatedmetabolites of [³ H]-5HT or [¹⁴ C]-β-phenethylamine. This procedureallows MAO-A and MAO-B activities to be measured either simultaneouslyor individually (3).

Procedure

A. Reagents

1. Phosphate buffer (0.5M), pH 7.4:

134.4 g NaH₂ PO₄.7H₂ O, bring to 1 liter in distilled H₂ O (A)

17.3 g Na₂ HPO₄, bring to 250 ml in distilled H₂ O (B)

Adjust pH of A to 7.4 by slowly adding B (volumes as needed)

Dilute 1:10 in distilled H₂₀ (0.05 M PO₄ buffer, pH 7.4)

2. 0.25M Sucrose (PO₄ buffered):

21.4 g sucrose, bring to 250 ml with 0.05M PO₄ buffer

3. Substrate for MAO-A:

a. Serotonin creatinine SO₄ (5HT) is obtained from Sigma ChemicalCompany.

A 5 mM stock solution is made up in 0.01N HCl. This is used to dilutethe specific activity of the [³ H]-5HT.

b. [³ H]-5-Hydroxytryptamine creatinine SO₄ (20-30 Ci/mmol) is obtainedfrom New England Nuclear.

c. Add 12 μl of [³ H]-5HT to 2 ml of the 5 mM 5HT solution. (Final amineconcentration in the assay is 200 μM: see below.)

4. Substrate for MAO-B

a. [3-phenethylamine (PEA) is obtained form Sigma Chemical Company. A 5mM stock solution is made up in 0.01 N HCl. This is used to dilute thespecific activity of the [¹⁴ C]-PEA.

b. β-[ethyl-1-¹⁴ C]-phenethylamine hydrochloride (40-50 mCi/mmol) isobtained from New England Nuclear.

c. Add 12 μl of [¹⁴ C]-PEA to 2 ml of the 5 mM PEA solution. (finalamine concentration in the assay is 200 μM: see below.)

5. Equal amounts of MAO-A (5HT) and MAO-B (PEA) substrates are combinedfor simultaneously testing both MAO types, i.e. mixed stock solution of2.5 mM 5HT and 2.5 mM PEA, 40 μl of this mixed solution gives a 200 μMfinal concentration of each amine in the assay. When testing only oneMAO type, the individual 5 mM stock solutions must be diluted 1:1 withdistilled water prior to adding 40 μl to the incubation mixture; i.e.,same 200 μM final amine concentration.

B. Tissue Preparation

Male Wistar rats weighing 150-250 grams were sacrificed and the brainsrapidly removed. Whole brain minus cerebellum was homogenized in 30volumes of ice-cold, phosphate-buffered 0.25M sucrose, using aPotter-Elvejhem homogenizer. The homogenate was centrifuged at 1000 gfor 10 minutes and the supernatant (S₁) decanted and recentrifuged at18,000 g for 20 minutes. The resulting pellet (P₂) was resuspended infresh 0.25M sucrose and served as the tissue source for mitochondrialMAO.

C. Assay

    ______________________________________    10 μl   0.5M PO.sub.4 buffer, pH 7.4    50 μl   H.sub.2 O or appropriate drug concentration    400 μl  Tissue suspension    ______________________________________

Tubes are preincubated for 15 minutes at 37° C. and the assay is startedby adding 40 μl of combined substrate ([³ H]-5HT and [¹⁴ C]-PEA) at 15second intervals. The tubes are incubated for 30 minutes at 37° C. andthe reaction stopped by the addition of 0.3 ml 2N HCl. Tissue blankvalues are determined by adding the acid before the radioactivesubstrate. The oxidative products of the reaction are extracted withethyl acetate/toluene (1:1). 5 ml of this mxiture is added to the tubes.The resultant mixture is vortexed for 15 seconds to extract thedeaminated metabolites into the organic phase and the latter is allowedto separate from the aqueous phase. The tubes are placed in acetone/dryice bath to freeze the aqueous layer. When this layer is frozen, the toporganic layer is poured into a scintillation vial. 10 ml of Liquiscintis added and the samples are counted using window settings for ¹⁴ C inone channel and 3H in the second channel. IC₅₀ values are determined bylog-probit analysis.

References

1. Johnston, J. P.: Some observations upon a new inhibitor of monoamineoxidase in brain tissue. Biochem. Pharmacol. 17:1285-1297 (1968).

2. Fowler, C. J. and Ross, S. B.: Selective inhibitors of monoamineoxidase A and B: biochemical, pharmacological and clinical properties.Med. Res. Rev. 4: 323-328 (1984).

3. Kindt, M. V., Youngster, S. K., Sonsalia, P. K., Duvoisin, R. C. andHeikkila, R. E.: Rose of monoamine oxidase-A (MOA-A) in thebioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTPanalog, 2'Me-MPTP. Eur. J. Pharmacol. 46: 313-318 (1988).

Results of the monoamine oxidase inhbition assay for representativecompounds of this invention are presented in Table II.

                  TABLE II    ______________________________________                      Inhibitory                      Concentration -                      IC.sub.50 (μM)                      MAO-A  MAO-B    ______________________________________    Compound    6-Methoxy-N-methyl-N-                        13       >10.sup.3    [2-(4-morpholinyl)ethyl]-    1,2-benzisoxazol-3-amine    6-Methoxy-N-[2-(methyl-                        25    amino)ethyl]-1,2-benzisoxazol-    3-amine    6-Methoxy-3-[1-(4-pyridyl)-                        10       45    piperazinyl]-1,2-benzisoxazole    (Reference Compound)    Brofaromine         0.18     23    ______________________________________

Ex vivo Monoamine Oxidase Inhibition Assay

The enzyme monoamine oxidase (MAO) exists in two catalyticallydistinguishable forms termed MAO-A and MAO-B. The ability of thecompounds of the invention to inhibit MAO ex vivo in the rat wasdetermined using a procedure adapted from the procedure set forth in TheJournal of Pharmacology and Experimental Therapeutics, Vol. 248, No. 1,(1989), pp. 400-414.

Procedure

The compound to be tested was administered to male Wistar rats orally.At specified times after administration the rats were decapitated andthe whole brain without cerebellum was dissected rapidly and frozen ondry ice. The samples were stored at -80° C. until measurement of the MAOactivity. After thawing, the tissues were homogenized in 5 volumes of0.1 mol/l of potassium-phosphate buffer, pH 7.4, using all glasshomogenisers. MAO activity was determined essentially as described byWurtman and Axelrod. Biochem. Pharmacol. 12: 1439-1441, (1963).

The enzyme reaction was started by addition of 80 μl of the MAO-Asubstrate [³ H]-5-HT (0.96 mCi/mmol, final amine concentration is 200 μMor of the MAO-B substrate [¹⁴ C]PEA (0.192 mCi/mmol, final amineconcentration is 200 μM and the incubation continued for 10 minutes at37° C. Then, the reaction was stopped by addition of 200 μl of 2N HCl,and the deaminated metabolites were extracted by vigorous shaking for 10minutes with 5 ml of diethylether (5-HT-extraction)or n-heptane(PEA-extraction). After centrifugation (1000×g; 30 sec) the water-phasewas frozen in dry ice and the organic layer poured into plastic vialscontaining 5 ml of scintillation cocktail. Finally, the radioactivitywas determined in a scintillation spectrometer. Reaction mixtures asdescribed above but lacking the homogenate served as blanks.

The results are presented in Table III.

                  TABLE III    ______________________________________                  Ex vivo inhibition (%) of                  monoamine oxidase                  at 50 mg/kg, p.o.    Compound        Type A   Type B     Time(h)    ______________________________________    3-[N-methyl, N-2-                    26       19         0.5    (morpholinyl)ethyl]amino-                    29       19         1.0    1,2-benzisoxazol-6-yl                    42       28         4.0    methylcarbamate 14       12         24.0    N-2-(4-morpholinyl)ethyl]-                    88       52         0.5    1,2-benzisoxazol-3-amine                    85       45         1.0                    68       33         4.0                    3.5      0.0        24.0    N-Methyl-N-2-(4-                    78       32         0.5    morpholinyl)ethyl]-1,2-                    66       25         1.0    benzisoxazole-3-amine                    76       36         4.0                    11       0          24.0    Meclobemide*    62       33         1.0    (Reference Compound)                    57       37         4.0                    14       9          24.0    ______________________________________     *administered at 10 mg/kg.

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsule or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric, 2-naphthalenesulfonic and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweeting agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension, These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present inventions are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in disposable syringes or multiple dose vials made ofglass or plastic.

The following examples will further illustrate this invention but arenot intended to limit it in anyway. In Tables IV and V, typicalcompounds of the present invention are listed. Following Table V,representative illustrative preparations of compounds of the inventionare described.

                                      TABLE IV    __________________________________________________________________________     ##STR31##    Ex    No      X             R.sup.1 m Z    __________________________________________________________________________    1 6-OCH.sub.3   CH.sub.3                            2                               ##STR32##                               ##STR33##    2 6-OH          CH.sub.3                            2                               ##STR34##    3 6-OC(O)NHCH.sub.3                    CH.sub.3                            2                               ##STR35##    4 6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                    CH.sub.3                            2                               ##STR36##    5 6-OC(O)NHCH(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR37##    6 H             CH.sub.3                            2                               ##STR38##    7 H             H       2                               ##STR39##    8 6-OCH.sub.3   H       2                               ##STR40##    9 6-OH          H       2                               ##STR41##    10      5-OH          H       2                               ##STR42##    11      6-OC(O)NHCH.sub.3                    H       2                               ##STR43##    12      5-OC(O)NHCH.sub.3                    H       2                               ##STR44##    13      6-OCH.sub.2 C.sub.6 H.sub.5                    H       2                               ##STR45##    14      6-NH.sub.2    H       2                               ##STR46##    15      6-NHC(O)CH.sub.3                    H       2                               ##STR47##    16      6-Cl          H       2                               ##STR48##    17      6-OC(O)CH.sub.3                    H       2                               ##STR49##    18      6-OC(O)N(CH.sub.3).sub.2                    H       2                               ##STR50##    19      6-OC(O)CH.sub.2 C.sub.6 H.sub.5                    H       2                               ##STR51##    20      6-OCH.sub.3   CH.sub.3                            2                               ##STR52##    21      6-OCH.sub.3   CH.sub.3                            3                               ##STR53##    22      6-OCH.sub.2 OCH.sub.3                    H       2                               ##STR54##    23      6-OH          H       2                               ##STR55##    24      6-OCH.sub.3   H       2 N(CH.sub.3).sub.2    25      5-OCH.sub.3   H       2                               ##STR56##    26      6-OC(O)NHCH.sub.3                    C(O)NHCH.sub.3                            2                               ##STR57##    27      5-OC(O)NHCH.sub.3                    C(O)NHCH.sub.3                            2                               ##STR58##    28      7-Br, 6-OCH.sub.3                    CH.sub.3                            2                               ##STR59##    29      5-Br, 6-OCH.sub.3                    H       2                               ##STR60##    30      6-OH          H       2                               ##STR61##    31      6-OCH.sub.3   CH.sub.3                            2                               ##STR62##    32      7-Br, 6-OH    CH.sub.3                            2                               ##STR63##    33      7-Br, 6-OC(O)N(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR64##    34      6-OCH.sub.3   CH.sub.3                            2                               ##STR65##    35      6-OH          CH.sub.3                            2                               ##STR66##    36      6-OC(O)NHCH.sub.3                    CH.sub.3                            2                               ##STR67##    37      6-OC(O)N(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR68##    38      6-OC(O)NHCH(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR69##    39      6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                    CH.sub.3                            2                               ##STR70##    40      6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                    CH.sub.3                            2                               ##STR71##    41       ##STR72##    CH.sub.3                            2                               ##STR73##    42      6-OH          CH.sub.3                            2                               ##STR74##    43      6-OC(O)NHCH.sub.3                    CH.sub.3                            2                               ##STR75##    44      6-OC(O)N(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR76##    45      6-OC(O)NHCH(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR77##    46      6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                    CH.sub.3                            2                               ##STR78##    47      6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                    CH.sub.3                            2                               ##STR79##    48       ##STR80##    CH.sub.3                            2                               ##STR81##    49      6-OCH.sub.3   CH.sub.3                            2                               ##STR82##    50      6-OH          CH.sub.3                            2                               ##STR83##    51      6-OC(O)NHCH.sub.3                    CH.sub.3                            2                               ##STR84##    52      6-OC(O)N(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR85##    53      6-OC(O)NHCH(CH.sub.3).sub.2                    CH.sub.3                            2                               ##STR86##    54      6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                    CH.sub.3                            2                               ##STR87##    55      6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                    CH.sub.3                            2                               ##STR88##    56       ##STR89##    CH.sub.3                            2                               ##STR90##    57      6-OCH.sub.3   H       2 NHCH.sub.3    58      6-OH          H       2 NHCH.sub.3    59      6-OC(O)NHCH.sub.3                    H       2 NHCH.sub.3    60      6-OC(O)N(CH.sub.3).sub.2                    H       2 NHCH.sub.3    61      6-OC(O)NHCH(CH.sub.3).sub.2                    H       2 NHCH.sub.3    62      6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                    H       2 NHCH.sub.3    63      6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                    H       2 NHCH.sub.3    64       ##STR91##    H       2 NHCH.sub.3    __________________________________________________________________________

                                      TABLE V    __________________________________________________________________________     ##STR92##    Ex    No X              Q    __________________________________________________________________________    65 6-OCH.sub.3                       ##STR93##    66 6-OH                       ##STR94##    67 6-OC(O)NHCH.sub.3                       ##STR95##    68 6-OC(O)N(CH.sub.3).sub.2                       ##STR96##    69 6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR97##    70 6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR98##    71 6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR99##    72        ##STR100##                       ##STR101##    73 6-OCH.sub.3                       ##STR102##    74 6-OH                       ##STR103##    75 6-OC(O)NHCH.sub.3                       ##STR104##    76 6-OC(O)N(CH.sub.3).sub.2                       ##STR105##    77 6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR106##    78 6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR107##    79 6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR108##    80        ##STR109##                       ##STR110##    81 6-OCH.sub.3                       ##STR111##    82 6-OH                       ##STR112##    83 6-OC(O)NHCH.sub.3                       ##STR113##    84 6-OC(O)N(CH.sub.3).sub.2                       ##STR114##    85 6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR115##    86 6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR116##    87 6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR117##    88        ##STR118##                       ##STR119##    89 6-OCH.sub.3                       ##STR120##    90 6-OH                       ##STR121##    91 6-OC(O)NHCH.sub.3                       ##STR122##    92 6-OC(O)N(CH.sub.3).sub.2                       ##STR123##    93 6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR124##    94 6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR125##    95 6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR126##    96        ##STR127##                       ##STR128##    97 6-OCH.sub.3                       ##STR129##    98 6-OH                       ##STR130##    99 6-OC(O)NHCH.sub.3                       ##STR131##    100       6-OC(O)N(CH.sub.3).sub.2                       ##STR132##    101       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR133##    102       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR134##    103       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR135##    104        ##STR136##                       ##STR137##    105       6-OCH.sub.3                       ##STR138##    106       6-OH                       ##STR139##    107       6-OC(O)NHCH.sub.3                       ##STR140##    108       6-OC(O)N(CH.sub.3).sub.2                       ##STR141##    109       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR142##    110       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR143##    111       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR144##    112        ##STR145##                       ##STR146##    113       6-OCH.sub.3                       ##STR147##    114       6-OH                       ##STR148##    115       6-OC(O)NHCH.sub.3                       ##STR149##    116       6-OC(O)N(CH.sub.3).sub.2                       ##STR150##    117       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR151##    118       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR152##    119       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR153##    120        ##STR154##                       ##STR155##    121       6-OCH.sub.3                       ##STR156##    122       6-OH                       ##STR157##    123       6-OC(O)NHCH.sub.3                       ##STR158##    124       6-OC(O)N(CH.sub.3).sub.2                       ##STR159##    125       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR160##    126       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR161##    127       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR162##    128        ##STR163##                       ##STR164##    129       6-OCH.sub.3                       ##STR165##    130       6-OH                       ##STR166##    131       6-OC(O)NHCH.sub.3                       ##STR167##    132       6-OC(O)N(CH.sub.3).sub.2                       ##STR168##    133       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR169##    134       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR170##    134       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR171##    136        ##STR172##                       ##STR173##    137       6-OCH.sub.3                       ##STR174##    138       6-OH                       ##STR175##    139       6-OC(O)NHCH.sub.3                       ##STR176##    140       6-OC(O)N(CH.sub.3).sub.2                       ##STR177##    141       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR178##    142       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR179##    143       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR180##    144        ##STR181##                       ##STR182##    145       6-OCH.sub.3                       ##STR183##    146       6-OH                       ##STR184##    147       6-OC(O)NHCH.sub.3                       ##STR185##    148       6-OC(O)N(CH.sub.3).sub.2                       ##STR186##    149       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR187##    150       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR188##    151       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR189##    152        ##STR190##                       ##STR191##    153       6-OCH.sub.3                       ##STR192##    154       6-OH                       ##STR193##    155       6-OC(O)NHCH.sub.3                       ##STR194##    156       6-OC(O)N(CH.sub.3).sub.2                       ##STR195##    157       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR196##    158       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR197##    159       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR198##    160        ##STR199##                       ##STR200##    161       6-OCH.sub.3                       ##STR201##    162       6-OH                       ##STR202##    163       6-OC(O)NHCH.sub.3                       ##STR203##    164       6-OC(O)N(CH.sub.3).sub.2                       ##STR204##    165       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR205##    166       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR206##    167       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR207##    168        ##STR208##                       ##STR209##    169       6-OCH.sub.3                       ##STR210##    170       6-OH                       ##STR211##    171       6-OC(O)NHCH.sub.3                       ##STR212##    172       6-OC(O)N(CH.sub.3).sub.2                       ##STR213##    173       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR214##    174       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR215##    175       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR216##    176        ##STR217##                       ##STR218##    177       6-OCH.sub.3                       ##STR219##    178       6-OH                       ##STR220##    179       6-OC(O)NHCH.sub.3                       ##STR221##    180       6-OC(O)N(CH.sub.3).sub.2                       ##STR222##    181       6-OC(O)NHCH(CH.sub.3).sub.2                       ##STR223##    182       6-OC(O)NHCH.sub.2 C.sub.6 H.sub.5                       ##STR224##    183       6-OC(O)NH(CH.sub.2).sub.6 CH.sub.3                       ##STR225##    184        ##STR226##                       ##STR227##    185       7-Br, 6-OH                       ##STR228##    186       7-Br, 6-OCH.sub.3                       ##STR229##    __________________________________________________________________________

EXAMPLE 16-Methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (6.0 g)and N-methyl-N-[2-(4-morpholinyl)ethyl]-amine (13.8 g). The reaction washeated to 140° C. over 48 hours and then cooled to room temperature. Theresidue was partitioned between ethyl acetate (EtOAc) and water,extracted again with EtOAc, and the organic phase was dried overmagnesium sulfate (MgSO₄) and concentrated in vacuo. Flash columnchromatography (silica gel) eluting with 1% methanol/dichloromethane(MeOH/DCM) provided the product (4.7 g), m.p. 43°-44° C.

ANALYSIS: Calculated for C₁₅ H₂₁ N₃ O₃ : 61.84%C 7.26%H 14.42%N Found:61.75%C 6.98%H 14.46%N

EXAMPLE 2 3-[[2-(4-Morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol

6-Methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine(7.0 g) was dissolved in 48% hydrobromic acid (130 ml) and heated toreflux under nitrogen for 3 hours. The reaction was cooled to roomtemperature, neutralized with saturated sodium carbonate (Na₂ CO₃)extracted with ethyl acetate, dried over MgSO₄ and concentrated invacuo. Flash chromatography (silica gel) eluting with 2:1heptane/acetone provided the product (6.0 g), m.p. 91°-92° C.

ANALYSIS: Calculated for C₁₄ H₁₉ N₃ O₃ : 60.63%C 6.91%H 15.15%N Found:60.36%C 6.94%H 14.96%N

EXAMPLE 3 3-[[2-(4-Morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ylmethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2 g) andcopper(I)chloride (0.3 g) in EtOAc (60 ml) was added methyl isocyanate(0.5 g). After 3.5 hours thin layer chromatography (TLC) (silica gel,10% MeOH/DCM) showed no starting material. The reaction was filteredthrough neutral alumina eluting with EtOAc (2 l) and the filtrate wasconcentrated in vacuo to yield 1.2 g of the product, m.p. 94°-95° C.

ANALYSIS: Calculated for C₁₆ H₂₂ N₄ O₄ : 57.47%C 6.63%H 16.76%N Found:57.61%C 6.67%H 16.60%N

EXAMPLE 4 3-[[2-(4-Morpholinyl)ethylmethylamino]-1,2-benzisoxazol-6-ylphenylmethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2.3 g)and 1,8 diazabicyclo[5.4.0]undec-7-ene (0.2 g) in EtOAc (80 ml) wasadded phenylmethyl isocyanate (1.3 g). After 24 hours an additionalequivalent of the isocyanate was added. TLC (silica gel, 10% MeOH/DCM)showed no starting material. The reaction was concentrated in vacuo.Flash chromatography (silica gel) eluting with 1% MeOH/DCM provided theproduct (2.4 g), m.p. 106°-107° C.

ANALYSIS: Calculated for C₂₂ H₂₆ N₄ O₄ : 64.38%C 6.38%H 13.65%N Found:64.34%C 6.34%H 13.55%N

EXAMPLE 5 3-[[2-(4-Morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-yl1-methylethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2.2 g)and copper(I)chloride (0.1 g) in EtOAc (50 ml) was added1-methylethylisocyanate (0.8 g). After 24 hours TLC (silica gel, 10%MeOH/DCM) showed no starting material. The reaction was filtered throughneutral alumina eluting with EtOAc (3 l) and the filtrate wasconcentrated in vacuo. The white solid was flash chromatographed onsilica gel eluting with 1% MeOH/DCM to yield 1.2 g of the product, m.p.99°-100° C.

ANALYSIS: Calculated for C₁₈ H₂₆ N₄ O₄ : 59.65%C 7.23%H 15.46%N Found:59.78%C 6.98%H 15.11%N

EXAMPLE 6 N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

To a sealed tube was added 3-chloro-1,2-benzisoxazole (3.0 g) andN-methyl-N-[2-(4-morpholinyl)ethyl]-amine (12.7 g). The reaction washeated to 140° C. over 72 hours and then cooled to room temperature. Theresidue was partitioned between EtOAc and water, extracted again withEtOAc, and the organic phase was dried over MgSO₄ and concentrated invacuo. Hash column chromatography (silica gel) eluting with 1-3%MeOH/DCM provided the product (1.2 g), as an oil.

ANALYSIS: Calculated for C₁₄ H₁₉ N₃ O₂ : 64.35%C 7.33%H 16.08%N Found:64.28%C 7.03%H 15.88%N

EXAMPLE 7 N-[2-(4-Morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

To a solution of 3-amino-1,2-benzisoxazole (3.5 g) inN,N-dimethylformamide (DMF) (100 ml) was added sodium hydride (0.8 g)under nitrogen. The reaction was stirred one hour at ambienttemperature. A solution of 4-(2-chloroethyl)morpholine (4.0 g) in DMF(50 ml) was added followed by heating to 120° C. for one hour. TLC (5%MeOH/DCM) analysis revealed the absence of starting material. Thereaction was quenched with water and extracted with EtOAc. The organiclayer was washed with water, dried (MgSO₄), and concentrated in vacuo.Flash column chromatography (silica gel) eluting with 1.5-2.5% MeOH/DCMafforded the product (2.5 g), m.p. 79°-80° C.

ANALYSIS: Calculated for C₁₃ H₁₇ N₃ O₂ : 63.14%C 6.93%H 16.99%N Found:63.47%C 6.87%H 16.95%N

EXAMPLE 8 6-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

a. 3-Amino-6-methoxy-1,2-benzisoxazole

METHOD A

To stirred solution of acetohydroxamic acid (24.6 g) in anhydrousN,N-dimethylformamide (400 ml) was added potassium tertiary butoxide(36.8 g) under nitrogen and stirring was continued for 1 hour.2-Fluoro-4-methoxybenzonitrile (33 g) was added to the reaction mixtureand stirring was continued for 6 hours. TLC (silica gel) with 10%acetone/chloroform showed no starting material. The reaction was dilutedwith ethyl acetate (˜3 L) and suction filtered. The filtrate wascollected and washed with brine (4×1 L); dried (MgSO₄) and concentratedin vacuo. The resulting solid was recrystallized fromdichloromethane/petroleum ether affording 20 g of product.

Alternatively, 4-methoxy-2-nitro-benzonitrile can be substituted for2-fluoro-4-methoxy benzonitrile to obtain the same product.

METHOD B

In 20 ml of DMF was dissolved acetone oxime (0.74 g), followed by sodiumhydride (0.30 g). After this mixture had stirred for 30 minutes,4-methoxy-2-nitro-benzonitrile (1.50 g) was added. After an additional30 minutes the reaction was poured into water (500 ml) and filtered. Thesolid was collected and dissolved in DCM (250 ml), dried (MgSO₄), andconcentrated in vacuo. The resulting solid was recrystallized fromethanol to yield 1.5 g of4-methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile, m.p. 78°-79°C.

ANALYSIS:

Calculated for C₁₁ H₁₂ N₂ O₂ : 64.69%C 5.92%H 13.72%N Found: 64.51%C5.77%H 13.49%N

Alternatively, 2-Fluoro-4-methoxy-benzonitrile can be substituted for4-methoxy-2-nitrobenzonitrile.

3-Amino-6-methoxy-1,2-benzisoxazole is prepared following substantiallythe procedure of Example 25a starting from4-methoxy-2-[[(1-methylethylidene)amino]-oxy]-benzonitrile.

4-Methoxy-2-[[(1-methylethylidene)amino]benzonitrile

In 20 ml of dry N,N-dimethylformamide was dissolved acetone oxime (0.74g) followed by sodium hydride (0.30 g). After this mixture has stirredfor 30 minutes, 4-methoxy-2-nitro-benzonitrile (1.50 g) was added. Afteran additional 30 minutes the reaction was poured into water (500 ml) andfiltered. The solid was collected and dissolved in dichloromethane (250ml), dried (MgSO₄), and concentrated in vacuo. The resulting solid wasrecrystallized from ethanol. The product (1.5 g), m.p. 141°-142° C.

ANALYSIS: Calculated for C₁₁ H₁₂ N₂ O₂ : 64.69%C 5.92%H 13.72%N Found:64.51%C 5.77%H 13.49%N

b. 6-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

To a solution of 3-amino-6-methoxy-1,2-benzisoxazole (5.5 g) inN,N-dimethylformamide (DMF) (100 ml) was added sodium hydride (1.2 g)under nitrogen. The reaction was stirred one hour at ambienttemperature. A solution of 4-(2-chloroethyl)morpholine (5.4 g) in DMF(50 ml) was added to the reaction and heated to 125° C. for one hour.TLC (5% MeOH/DCM) revealed the absence of starting material. Thereaction was quenched with water (1 l) and extracted with EtOAc (2 l).The organic layer was washed with water, dried (MgSO₄), and concentratedin vacuo. Flash column chromatography (silica gel) eluting with 3-4%MeOH/DCM afforded the product (4.5 g), m.p. 85°-86° C.

ANALYSIS:

Calculated for C₁₄ H₁₉ N₃ O₃ : 60.63%C 6.91%H 15.15%N Found: 60.55%C6.97%H 15.28%N

EXAMPLE 9 3-[[2-(4-Morpholinyl]amino]-1,2-benzisoxazol-6-ol

6-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine (2.9 g)was dissolved in 48% hydrobromic acid (50 ml) and heated to reflux undernitrogen for 3 hours. The reaction was cooled to room temperature,neutralized with saturated sodium carbonate (Na₂ CO₃) solution, andextracted with EtOAc. The organic phase was dried over MgSO₄ andconcentrated in vacuo. Flash chromatography (silica gel) during with 3:2acetone/heptane and subsequently titration with DCM/heptane provided theproduct (1.0 g), m.p. 151°-152° C.

ANALYSIS:

Calculated for C₁₃ H₁₇ N₃ O₃ : 59.30%C 6.51%H 15.96%N Found: 58.97%C6.56%H 15.95%N

EXAMPLE 10 3-[[2-(4-Morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-5-ol

5-Methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine(2.6 g) was dissolved in 48% hydrobromic acid (40 ml) and heated toreflux under nitrogen for 6 hours. The reaction was cooled to roomtemperature, neutralized with saturated Na₂ CO₃ solution, and extractedwith EtOAc. The organic phase was dried over MgSO₄ and concentrated invacuo. Flash chromatography (silica gel) eluting with 1:1:20acetone/MeOH/DCM provided the pure product (2.1 g), 153°-154° C.

ANALYSIS: Calculated for C₁₃ H₁₇ N₃ O₃ : 59.30%C 6.51%H 15.96%N Found:59.00%C 6.50%H 15.78%N

EXAMPLE 11 3-[[2-(4-Morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ylmethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol (2 g) andcopper(I)chloride (0.3 g) in EtOAc (60 ml) was added methyl isocyanate(0.5 g). After 3.5 hours TLC (silica gel, 10% MeOH/DCM) showed nostarting material. The reaction was filtered through neutral aluminaeluting with EtOAc (2 l) and the filtrate was concentrated in vacuo.Flash column chromatography (silica gel) eluting with 1:1:20acetone/MeOH/DCM afforded a white solid which was recrystallized fromEtOAc/pet. ether to yield 0.7 g of the expected product, m.p. 127°-128°C.

ANALYSIS: Calculated for C₁₅ H₂₀ N₄ O₄ : 56.24%C 6.29%H 17.49%N Found:56.25%C 6.32%H 17.55%N

EXAMPLE 12 3-[[2-(4-Morpholinyl)ethyl]amino]-1,2-benzisoxazol-5-ylmethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]-amino]-1,2-benzisoxazol-5-ol (1 g) and acatalytic amount of copper(I)chloride (0.05 g) in EtOAc (100 ml) wasadded methyl isocyanate (0.26 g). After 24 hours TLC (silica gel, 1:1:20acetone/MeOH/DCM) showed no starting material. The reaction was filteredthrough neutral alumina during with EtOAc (1 l) and the filtrate wasconcentrated in vacuo. The residue was further purified by flashchromatography (silica gel) eluting with 1:1:20 acetone/MeOH/DCM toyield 0.4 g of the product, m.p. 135°-136° C.

ANALYSIS: Calculated for C₁₅ H₂₀ N₄ O₄ : 56.24%C 6.29%H 17.49%N Found:56.09%C 6.25%H 17.50%N

EXAMPLE 16 6-Chloro-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

a. 4-Chloro-2-[[(1-methylethylidene)amino]oxy]benzonitrile

In 75 ml of dry N,N-dimethylformamide was dissolved acetone oxime (1.21g), followed by potassium tertiaryl butoxide (1.85 g) and stirred undernitrogen. After 30 minutes, 4-chloro-2-nitro-benzonitrile (2.00 g) wasadded. After an additional 30 minutes the reaction was poured into water(500 ml) and filtered. The solid was collected and dissolved in DCM (250ml), dried (MgSO₄), and concentrated in vacuo. The resulting solid wasrecrystallized from ethanol to yield 1.5 g of the product, m.p. 83°-84°C.

ANALYSIS: Calculated for C₁₀ H₉ N₂ OCl: 57.57%C 4.35%H 13.43%N Found:57.52%C 3.95%H 13.33%N

b. 3-Amino-6-chloro-1,2-benzisoxazole

3-Amino-6-chloro-1,2-benzisoxazole is prepared from the product ofExample 16a following substantially the procedure of Example 25a.

Alternatively, the same product is obtained from4-chloro-2-nitrobenzonitrile or 2-fluoro-4-chlorobenzonitrile.

c. 6-Chloro-N-2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

6-Chloro-N-[2,4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine is preparedfrom the product of Example 16b following substantially the procedure ofExample 8a.

EXAMPLE 18 3-[[2-(4-Morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-yldimethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol (Example 9) (1.5g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 g) in 1,2-dichloroethane(40 ml) was added dimethylcarbamyl chloride (0.65 g). The mixture wasrefluxed for 24 hours under N₂. TLC (silica gel, 10% MeOH/DCM) showed nostarting material. The reaction was filtered and the filtrateconcentrated in vacuo. Flash chromatography (silica gel) eluting with 5%acetone/5% MeOH/CH₂ Cl₂ provided a residue which upon crystallizationafforded 0.5 g of the product, m.p. 150° C.

ANALYSIS: Calculated for C₁₆ H₂₂ N₄ O₄ : 57.47%C 6.63%H 16.76%N Found:56.97%C 6.36%H 16.67%N

EXAMPLE 226-Methoxymethoxy-N-[2-(4-thiomorpholinyl)ethyl]-1,2-benzisoxazol-3-amine

a. 3-Amino-6-(methoxymethoxy)-1,2-benzisoxazole

To a stirred solution of acetohydroxamic acid (3.88 g) inN,N-dimethylformamide (DMF) (120 ml) was added potassiumtertiarybutoxide (tBuOK) (5.80 g) under N₂. After one hour of stirring2-fluoro-4-(methoxymethoxy)-benzonitrile (6.0 g) was added. Stirringcontinued for 16 hours. TLC (silica gel) in 10% acetone/CHCl₃ showed thepresence of starting material. An additional 1 equivalent ofacetohydroxamic acid and tBuOK were added in DMF (120 ml). After onehour the reaction was diluted with EtOAc (2 l), filtered, washedfiltrate with brine (4×11), dried (MgSO₄), and concentrated in vacuo.Flash column chromatography (silica gel) was performed eluting with 2.5%acetone/CH₂ Cl₂ solution affording 8.1 g of the product, m.p. 88°-89° C.

ANALYSIS: Calculated for C₉ H₁₀ N₂ O₃ : 55.67%C 5.19%H 14.32%N Found:55.73%C 4.80%H 14.29%N

b.6-Methoxymethoxy-N-[2-(4-thiomorpholinyl)ethyl]-1,2-benzisoxazol-3-amine

To a solution of 3-amino-6-methoxymethoxy-1,2-benzisoxazole (4.0 g) inN,N-dimethylformamide (DMF) (50 ml) was added sodium hydride (0.74 g)under nitrogen. The reaction was stirred one hour at ambienttemperature. A solution of 4-(2-chloroethyl)thiomorpholine (3.6 g) inDMF (25 ml) was added to the reaction and heated to 125° C. for threehours. TLC (5% MeOH/CH₂ Cl₂) revealed the absence of starting material.The reaction was diluted with EtOAc (1 l), washed with brine (4×500 ml),dried (MgSO₄), and concentrated in vacuo. Flash column chromatography(silica gel) eluting with 5% acetone/CH₂ Cl₂ afforded the the product(2.0 g).

ANALYSIS: Calculated for C₁₅ H₂₁ N₃ O₃ S: 55.71%C 6.54%H 12.99%N Found:55.21%C 6.65%H 12.58%N

EXAMPLE 25 5-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

a. 5-Methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile

In 400 ml of DMF was dissolved acetone oxime (34.5 g) followed bypotassium t-butoxide (51 g). After this mixture had stirred for 30minutes, 5-methoxy-2-nitro-benzonitrile (70 g) was added. After stirringovernight, the reaction was diluted with ether (˜4 L) and filtered. Thefiltrate was washed with ethyl acetate and combined organics were washedwith water (3×1.5 L), dried (MgSO₄) and concentrated in vacuo.Preparative liquid chromatography (silica gel) eluting with 4:1heptane/EtOAc yielded the expected product (10 g).

b. 3-Amino-5-methoxy-1,2-benzisoxazole

In 125 ml of dry methanol was dissolved5-methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile (10 g),followed by 125 ml of ethereal hydrochloric acid. The reaction wasstirred under nitrogen overnight. The reaction was neutralized withsaturated sodium carbonate solution and extracted with EtOAc. Theorganic layer was dried and concentrated in vacuo. Recrystallization ofthe residue from dichloromethane/petroleum ether afforded the expectedproduct (6.8 g).

c. 5-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzosoxazol-3-amine

5-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazole-3-amine wasprepared from the product of Example 25b following substantially theprocedure of Example 8b.

EXAMPLE 263-[[(Methylamino)carbonyl][2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ylmethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol (Example 9)(1.77 g) and a catalytic amount of copper(I)chloride (0.05 g) in EtOAc(150 ml) was added methyl isocyanate (0.46 g). After 24 hours TLC(silica gel, 1:1:20 acetone/MeOH/DCM) showed no starting material. Thereaction was filtered through neutral alumina eluting with 10%MeOH/EtOAc (2 l) and the filtrate was concentrated in vacuo. The residuewas further purified by flash chromatography (silica gel) eluting 1:1:20acetone/MeOH/DCM. The resulting solid was recrystallized from EtOAc/pet.ether to afford 0.5 g of the product, m.p. 138°-139° C.

ANALYSIS: Calculated for C₁₇ H₂₃ N₅ O₅ : 54.10%C 6.14%H 18.56%N Found:54.08%C 6.34%H 18.61%N

EXAMPLE 273-[[(Methylamino)carbonyl][2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-5-ylmethylcarbamate

To a stirred solution of3-[[2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-5-ol (Example 10) (1g) and a catalytic amount of copper(I)chloride (0.05 g) in EtOAc (100ml) was added methyl isocyanate (0.26 g). After 24 hours TLC (silicaget, 1:1:20 acetone/MeOH/DCM) showed no starting material. The reactionwas filtered through neutral alumina eluting with EtOAc (2 l) and thefiltrate was concentrated in vacuo. The residue was further purified byflash chromatography (silica gel) eluting with 1:1:20 acetone/MeOH/DCM.The resulting solid was recrystallized from EtOAc/pet. ether to afford0.6 g of the product, m.p. 141°-142° C.

ANALYSIS: Calculated for C₁₇ H₂₃ N₅ O₅ : 54.10%C 6.14%H 18.56%N Found:54.3 ! %C 6.26%H 18.66%N

EXAMPLE 287-Bromo-6-methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

a. 7-Bromo-3-chloro-6-methoxy-1,2-benzisoxazole

To a stirred solution of 3-chloro-6-methoxy-1,2-benzisoxazole (25 g) inacetic acid (200 ml) was added a solution of bromine (32.6 g) in aceticacid (100 ml) dropwise under N₂ at ambient temperature. The mixture wasallowed to stir overnight. TLC (silica gel, 5% acetone/CCl₄) revealedthe presence of starting material. Additional bromine (11 g) in aceticacid (50 ml) was added, and the reaction mixture was allowed to stirovernight. The reaction was filtered and washed with water. Theprecipitate was collected and recrystallized from methanol to yield thedesired compound, m.p. 134°-135° C.

ANALYSIS: Calculated for C₈ H₅ NO₂ BrCl: 36.61%C 1.92%H 5.34%N Found:36.49%C 1.87%H 5.40%N

b.7-Bromo-6-methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

7-Bromo-6-methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amineis obtained from the compound of Example 28a following substantially theprocedure of Example 1.

EXAMPLE 295-Bromo-6-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

a. 3-Amino-5-bromo-6-methoxy-1,2-benzisoxazole

To a stirred solution of 3-amino-6-methoxy-1,2-benzisoxazole (14 g) inmethanol (1 L) was added a solution of bromine (13.6 g) and methanol(200 ml) dropwise at -50° C. under N₂. The mixture was allowed to warmto room temperature after the addition was complete. After 24 hours anadditional 1/4 equivalent of bromine was added. TLC (10% acetone/CHCl₃)showed no starting material 24 hours later. The reaction was neutralizedwith saturated K₂ CO₃ solution, treated with saturated Na₂ SO₃ solutiontriturated with water, filtered, and washed with water. The crudeproduct was dried in vacuo affording 14 g of product, m.p. 226°-227° C.

ANALYSIS: Calculated for C₈ H₇ N₂ O₂ Br: 39.53%C 2.90%H 11.53%N Found:39.93%C 2.59%H 11.42%N

b. 5-Bromo-6-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine

5-Bromo-6-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine isprepared from the compound of Example 29(a) following substantially theprocedure used in Example 8(b).

EXAMPLE 30 3-[[2-(4-Thiomorpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol

6-Methoxymethoxy-N-[2-(4-thiomorpholinyl)ethyl]-1,2-benzisoxazol-3-amine(1.6 g Example 22) was dissolved in methanolic hydrochloric acid (40 ml)and stirred under nitrogen for 24 hours. The reaction was neutralizedwith saturated Na₂ CO₃ solution, and extracted with EtOAc. The organicphase was dried over MgSO₄ and concentrated in vacuo. The resultingresidue was filtered through a silica gel filter-cake eluting with 5%MeOH/DCM, concentrated in vacuo, and subsequent titration with EtOAcprovided the product (1.0 g).

ANALYSIS: Calculated for C₁₃ H₁₇ N₃ O₂ S: 55.89%C 6.13%H 15.04%N Found:55.68%C 5.89%H 14.61%N

EXAMPLE 316-Methoxy-N-methyl-N-[2-[4-(1-phenylmethyl)piperdinyl]ethyl]-1,2-benzisoxazol-3-aminesesquihydrochloride

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (1.0 g)and 4-(2-methylaminoethyl)-1-phenylmethylpiperdine (5.0 g). The reactionwas heated to 140° C. over 72 hours and then cooled to room temperature.The residue was partitioned between EtOAc and brine, washed with brine(4×), and the organic phase was dried over MgSO₄ and concentrated invacuo. Flash column chromatography (silica gel) eluting with 5%acetone/CH₂ Cl₂ provided a residue upon evaporization (0.6 g) which wasdissolved in ether and made acidic with ethereal hydrochloric acid. Theprecipitate was dried in vacuo to yield 1.2 g of the expected product.

ANALYSIS: Calculated for C₂₃ H₂₉ N₃ O₂.3/2 HCl: 63.62%C 7.08%H 9.68%NFound: 63.40%C 6.84%H 9.44%N

EXAMPLE 32 7-Bromo-3-[N-methyl,N-2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-6-ol

A stirred solution of7-bromo-6-methoxy-N-methyl-N-[2-(morpholinyl)ethyl]-1,2-benzisoxazol-3-amine(4.0 g), and lithium bromide (4.7 g) in N,N-dimethylformamide (DMF) (100ml) was heated to reflux under N₂ for 3 hours. The reaction was dilutedwith EtOAc (11), filtered, washed with brine (4×), dried over MgSO₄, andconcentrated in vacuo. Flash column chromatography (silica gel) elutingwith 1:1:40 acetone/MeOH/CH₂ Cl₂ afforded 1 g of material. The meltingpoint was 186°-187° C.

EXAMPLE 33 7-Bromo-3-[N-methyl,N-2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-6-yl dimethylcarbamate

To a stirred solution of 7-bromo-3-[N-methyl,N-2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-6-ol (0.7 g) and 1,8diazabicyclo[5.4.0]undec-7-ene (0.09 g) in 1,2-dichloroethane (30 ml)was added dimethylcarbamyl chloride (0.25 g). The mixture was refluxedfor 24 hours under N₂. TLC (silica gel, 10% MeOH/DCM) showed somestarting material. An additional 1/2 equivalent of dimethylcarbamylchloride was added and refluxed for 24 more hours. The reaction wasfiltered and the filtrate concentrated in vacuo. Flash chromatography(silica gel) eluting with 5% acetone/5% MeOH/CH₂ Cl₂ provided a residuewhich upon crystallization afforded 0.5 g of the expected compound.

ANALYSIS: Calculated for C₁₇ H₂₃ N₄ O₄ Br: 47.79%C 5.43%H 13.11%N Found:47.77%C 5.42%H 12.86%N

EXAMPLE 346-Methoxy-N-methyl-N-[2-(2-pyridyl)ethyl]-1,2-benzisoxazol-3-aminehydrochloride hemihydrate

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (2.5 g)and 2-(2-methylaminoethyl)pyridine (11.0 g). The reaction was heated to140° C. over 72 hours and then cooled to room temperature. The residuewas partitioned between EtOAc and brine, washed with brine (4×), and theorganic phase was dried over MgSO₄ and concentrated in vacuo.Preparative liquid chromatography (silica gel) eluting with 5%acetone/CH₂ Cl₂ provided a residue upon evaporation (1.5 g) which wasdissolved in ether and made acidic with ethereal hydrochloric acid. Theprecipatate was dried in vacuo and recrystallized from ethanol to yield0.9 g, m.p. 152°-153° C.

ANALYSIS: Calculated for C₁₆ H₁₇ N₃ O₂.HCl.1/2H₂ O: 61.84%C 7.26%H14.42%N Found: 61.75%C 6.98%H 14.46%N

Examples 35-41 are prepared starting with the compound of Example 34following substantially the procedures set forth in Examples 2-5 and 18.

Examples 42-48 are prepared from Example 31 following substantially theprocedures set forth in Examples 2-5 and 18.

EXAMPLE 496-Methoxy-N-methyl-N-[2-[1-(4-phenylmethyl)piperazinyl]ethyl]-1,2-benzisoxazol-3-amineDifumarate

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (1.32 g)and 1-(2-methylaminoethyl)-4-phenylmethylpiperazine (6.7 g). Thereaction was heated to 140° C. over 24 hours and then cooled to roomtemperature. The residue was partitioned between EtOAc and brine, washedwith brine (4×) and the organic phase was dried over MgSO₄ andconcentrated in vacuo. Flash column chromatography (silica gel) elutingwith 2.5% MeOH/EtOAc provided a residue upon evaporation (0.8 g) whichwas dissolved in ether and made acidic with ethereal fumaric acid. Theprecipatate was dried in vacuo to yield 1.0 g, m.p. 215°-216° C.

ANALYSIS: Calculated for C₂₂ H₂₈ N₄ O₂.2C₄ H₄ O₄ : 58.82%C 5.92%H 9.15%NFound: 59.26%C 5.78%H 9.43%N

Examples 50-56 are prepared starting from the compound of Example 49 andfollowing substantially the procedure set forth in Examples 2-5 and 18.

EXAMPLE 57 6-Methoxyl-N-[2-(methylamino)ethyl)-1,2-benzisoxazol-3-amine

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (2.0 g)and N-methylethylenediamine (4.8 g). The reaction was heated to 140° C.over 48 hours and then cooled to room temperature. The residue waspartitioned between EtOAc and brine, washed with brine (4×) and theorganic phase was dried over MgSO₄ and concentrated in vacuo. Flashchromatography (silica gel) eluting with 5% acetone/CH₂ Cl₂ provided aresidue upon evaporation (0.4 g) m.p. 136°-137° C.

ANALYSIS: Calculated for C₁₁ H₁₅ N₃ O₂ : 59.71%C 6.83%H 18.99%N Found:59.52%C 6.68%H 18.54%N

Examples 58-64 are prepared starting from the compound of Example 57following substantially the procedure set forth in Examples 2-5 and 18.

EXAMPLE 65 6-Methoxy-3-(1-piperazinyl)-1,2-benzisoxazole hemihydrate

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (3.0 g)and piperazine (6.0 g). The reaction was heated to 140° C. over 4 hoursand then cooled to room temperature. The residue was dissolved in MeOHand further diluted with EtOAc (11). The precipatate was filtered andthe filtrate dried over MgSO₄ and concentrated in vacuo. Flashchromatography (silica gel) eluting with 30% MeOH/EtOAc provided aresidue upon evaporation (3.6 g), m.p. 79°-80° C.

ANALYSIS: Calculated for C₁₂ H₁₅ N₃ O₂.1/2H₂ O: 59.49%C 6.65%H 17.34%NFound: 59.25%C 6.28%H 17.30%N

Examples 66 to 72 are prepared from the compound of Example 65 followingsubstantially the procedures set forth in Examples 2-5 and 18.

EXAMPLE 73 6-Methoxy-3-[1-(4-aminomethyl)piperidyl]-1,2-benzisoxazole

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (2.0 g)and 4-aminomethylpiperidine (6.2 g). The reaction heated to 140° C. for24 hours and monitored by TLC (silica gel) (30% MeOH/EtOAc) wascomplete. The reaction was diluted in MeOH and concentrated in vacuo.The resulting residue was flash chromatographed (silica gel) elutingwith 30% MeOH/EtOAc affording a white, solid after evaporation. Thesolid was recrystallized from 15% MeOH/EtOAc/pet. ether to yield 1.0 g,m.p. 89°-90° C.

ANALYSIS: Calculated for C₂₈ H₃₁ N₃ O₂ : 64.35%C 7.33%H 16.08%N Found:64.26%C 7.49%H 16.20%N

Examples 74-80 are prepared starting from the compound of Example 73 andfollowing substantially the procedure set forth in Examples 2-5 and 18.

EXAMPLE 816-Methoxy-3-[1-[4-(N,N-diphenylmethyl)aminomethyl]piperidyl]-1,2-benzisoxazole

To a stirred solution of6-methoxy-3-[1-(4-aminomethyl)piperidyl]-1,2-benzisoxazole (1.0 g),triethylamine (0.8 g) in CH₂ Cl₂ (30 ml) was added α-bromotoluene (1.3g) under N₂. The reaction was monitored after 24 hours by TLC (silica)(10% MeOH/CH₂ Cl₂) and was complete. The reaction was diluted with CH₂Cl₂ (30 ml), washed with water and brine, dried over MgSO₄, andconcentrated in vacuo. Flash column chromatography (silica gel) elutingwith 5% MeOH/EtOAc provided a solid upon evaporation which wasrecrystallized from CH₂ Cl₂ /pet. ether to yield 0.25 g, m.p. 107°-108°C.

ANALYSIS: Calculated for C₂₈ H₃₁ N₃ O₂ : 76.16%C 7.08%H 9.52%N Found:76.23%C 7.40%H 9.66%N

Examples 82-88 are prepared starting from the compound of Example 81 andfollowing substantially the procedure set forth in Examples 2-5 and 18.

EXAMPLE 89 6-Methoxy-3-[1-[4-(2-propynyl)]piperazinyl]-1,2-benzisoxazole

To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(1.32 g), triethylamine (0.63 g) in CH₂ Cl₂ (75 ml) was added3-bromopropyne (1.42 g) under N₂. After 24 hours the reaction monitoredby TLC (silica gel) (5% MeOH/EtOAc) was complete. The reaction waswashed with brine, and water, dried over MgSO₄ and concentrated invacuo. The resulting residue was flash chromatographed (silica gel)eluting with 2.5% MeOH/EtOAc affording a white solid after evaporation.The solid was recrystallized from CH₂ Cl₂ /pet. ether. The product (0.4g) m.p. 114°-115° C.

ANALYSIS: Calculated for C₁₅ H₁₇ N₃ O₂ : 66.40%C 6.32%H 15.49%N Found:66.03%C 6.02%H 15.45%N

Examples 90-96 are prepared starting from the compound of Example 89 andfollowing substantially the procedure set forth in Examples 2-5 and 18.

EXAMPLE 97 6-Methoxy-3-[1-(N-phenyl)piperazinyl]-1,2-benzisoxazole

A sealed tube was charged with 3-chloro-6-methoxy-1,2-benzisoxazole(0.75 g, 4.1 mmol) and N-phenylpiperazine (2.65 g, 16 mmol) and heatedto 140° C. overnight. The reaction was cooled to room temperature,diluted with methanol, and concentrated in vacuo. The material was flashchromatographed (silica gel) eluting with 2:1 CH₂ Cl₂ /heptane to yielda white solid 0.40 g, m.p.=120°-121° C., white solid.

ANALYSIS: Calculated for C₁₈ H₁₉ N₃ O₂ : 69.88%C 6.19%H 13.58%N Found:69.67%C 6.15%H 13.61%N

Examples 98-104 are prepared starting from the compound of Example 97and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 105 6-Methoxy-3-[1-(4-pyridyl)piperazinyl)]-1,2-benzisoxazole

To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(1.0 g) in DMF (30 ml) was added 4-chloropyridine hydrochloride (0.96 g)under N₂ at 120° C. After 4 hours the reaction monitored by TLC (silicagel) (30% MeOH/EtOAc) was complete. The reaction was concentrated invacuo. The resulting residue was flash chromatographed (silica gel)eluting with 10% MeOH/CH₂ Cl₂ affording a white solid after evaporation.The solid was recrystallized from 15% MeOH/EtOAc/heptane to yield 0.3 g,m.p. 154°-155° C.

ANALYSIS: Calculated for C₁₇ H₁₈ N₄ O₂ : 65.79%C 5.85%H 18.05%N Found:65.84%C 5.33%H 17.95%N

EXAMPLE 106 3-[1-(4-Pyridyl)piperazinyl]-1,2-benzisoxazol-6-ol

A stirred solution of6-methoxy-3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazole (1.75 g) andsodium ethylthiolate (0.79 g) in DMF (30 ml) was heated to 105°-107° C.under N₂ for 3 hours. TLC (silica gel 30% MeOH/CH₂ Cl₂) showed nopresence of starting material. Glacial acetic acid (5 ml) was added andthe solvent was removed in vacuo. The residue was flash chromatographed(silica gel) eluting with 10% MeOH/CH₂ Cl₂ to afford 1.1 g of material.The material was further purified through recrystallization frompyridine to afford 1.0 g of the product, m.p.>250° C.

ANALYSIS: Calculated for C₁₆ H₁₆ N₄ O₂ : 64.85%C 5.44%H 18.91%N Found:64.84%C 5.42%H 18.67%N

EXAMPLE 108 3-[1-(4-Pyridyl)piperazinyl]-1,2-benzisoxazol-6-yldimethylcarbamate

To a stirred solution of3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazol-6-ol (0.80 g) in pyridine(10 ml) was added dimethylcarbamyl chloride (0.70 g) under N₂. Thereaction was heated to 85° C. for 2 hours. TLC (silica gel 30% MeOH/CH₂Cl₂) showed no starting material was present. The solvent was removed invacuo and the residue was flash chromatographed (silica gel) elutingwith 7% MeOH/CH₂ Cl₂ to afford 0.80 g of material. The material wasfurther purified through recrystallization from CH₂ Cl₂ /pet. ether toafford 0.70 g of the product, m.p. 171°-172° C.

ANALYSIS: Calculated for C₁₉ H₂₁ N₅ O₃ : 62.11%C 5.76%H 19.06%N Found:61.91%C 5.83%H 18.76%N

Examples 107 and 109-112 are prepared starting from the compound ofExample 106 and following substantially the procedure set forth inExamples 2-5 and 18.

EXAMPLE 113 6-Methoxy-3-[1-(2-pyridyl)piperazinyl]-1,2-benzisoxazole

A sealed tube was charged with 3-chloro-6-methoxy-1,2-benzisoxazole(0.25 g, 1.4mmol) and 1-(2-pyridyl)piperazine (0.67 g, 4 mmol) andheated to 140° C. overnight. The reaction was cooled to roomtemperature, diluted with methanol, and concentrated in vacuo. Thematerial was flash chromatographed (silica gel) eluting with CH₂ Cl₂.The material was further purified through recrystallization from1,2-dichloroethane/pet. ether to afford 0.15 g of the product,m.p.=123°-124° C.

ANALYSIS: Calculated for C₁₇ H₁₈ N₄ O₂ : 65.79%C 5.85%H 18.05%N Found:65.43%C 5.56%H 17.67%N

Examples 114-120 are prepared starting from the compound of Example 113and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 1213-[1-(4-(6-Chloropyrimidyl)piperazinyl]-6-methoxy-1,2-benzisoxazole

A stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole (1.0g), 4,6-dichloropyrimidine (0.64 g) and sodium bicarbonate (1.08 g) wererefluxed in absolute ethanol under N₂ for 90 minutes. TLC (silica gel2/1 acetone/heptane) showed no presence of starting material. Thereaction was allowed to cool to room temperature, partitioned betweenCH₂ Cl₂ and water, extracted with CH₂ Cl₁₂, dried over MgSO₄ andconcentrated in vacuo to afford 1.44 g of material. The material wasfurther purified through recrystallization from CH₂ Cl₂ /pet. ether toyield the product 1.1 g, m.p. 203°-204° C.

ANALYSIS: Calculated for C₁₆ H₁₆ N₅ O₂ Cl: 55.58%C 4.66%H 20.25%N Found:55.57%C 4.66%H 20.02%N

Examples 122-128 are prepared starting from the compound of Example 121and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 1293-[1-(2-(6-Chloro)pyrazinyl)piperazinyl]-6-methoxy-1,2-benzisoxazole

A stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole (1.0g, 4.3 mmol) in DMF (10 ml) was added 2,6-dichloropyrazine (0.95 g, 6.4mmol) under N₂. The reaction was heated to 140° C. for 4 hours andconcentrated in vacuo. The material was filtered, washing with CH₂ Cl₂,washings were collected, and concentrated in vacuo. The residue wasflash chromatographed (silica gel) eluting with 5% acetone/CH₂ Cl₂ toyield a white solid 0.50 g, m.p. 175°-176° C.

ANALYSIS: Calculated for C₁₆ H₁₆ N₅ O₂ Cl: 55.58%C 4.66%H 20.25%N Found:55.41%C 4.60%H 20.18%N

Examples 130-136 are prepared starting from the compound of Example 129and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 1373-[1-(3-(6-Chloro)pyridazinyl)piperazinyl]-6-methoxy-1,2-benzisoxazole

To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(1.0 g, 4.3 mmol) in DMF (10 ml) was added 3,6-dichloropyridazine (0.95g, 6.4 mmol) under N₂. The reaction was heated to 140° C. overnight. Thereaction was allowed to cool to room temperature and concentrated invacuo. The material was recrystallized from ethanol to afford 0.70 g,m.p.=237°-238° C.

ANALYSIS: Calculated for C₁₆ H₁₆ N₅ O₂ Cl: 55.58%C 4.66%H 20.25%N Found:55.72%C 4.29%H 20.17%N

Examples 138-144 are prepared starting from the compound of Example 137and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 1456-Methoxy-3-[1-(4-phenylmethyl)piperazinyl]-1,2-benzisoxazole

To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (2.0 g)and N-phenylmethylpiperazine (7.7 g). The reaction was heated to 140° C.for 24 hours and monitored by TLC (silica gel) (5% MeOH/EtOAc) wascomplete. The reaction was diluted in MeOH and EtOAc (1:4), washed withbrine, dried over MgSO₄ and concentrated in vacuo. The resulting residuewas flash chromatographed (silica gel) eluting with 5% MeOH/CH₂ Cl₂affording a white solid after evaporation. The solid was recrystallizedfrom CH₂ Cl₂ /pet. ether to yield 2.5 g, m.p. 99°-100° C.

ANALYSIS: Calculated for C₁₉ H₂₁ N₃ O₂ : 70.57%C 6.55%H 12.99%N Found:70.41%C 6.54%H 13.04%N

Examples 146-152 are prepared starting from the compound of Example 145and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 1536-Methoxy-3-[1-[4-(3-methyl)phenylmethyl]piperazinyl]-1,2-benzisoxazole

To a sealed tube was added 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(1.04 g), triethylamine (0.68 g) in CH₂ Cl₂ (100 ml) was addedα-bromo-m-xylene (0.91 g) under N₂. After 24 hours the reactionmonitored by TLC (silica gel) was complete. The reaction was washed withwater and brine, dried over MgSO₄, and concentrated in vacuo. Theresulting residue was flash chromatographed (silica gel) eluting with10% acetone/CH₂ Cl₂ affording a white solid after evaporation. The solidwas recrystallized from CH₂ Cl₂ /pet. ether to yield 0.3 g, m.p.106°-106° C.

ANALYSIS: Calculated for C₂₀ H₂₃ N₃ O₂ : 71.19%C 6.87%H 12.45%N Found:71.11%C 6.75%H 12.39%N

Examples 154-160 are prepared starting from the compound of Example 153and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 161 6-Methoxy-3-[1-(4-quinolinyl)piperazinyl]-1,2-benzisoxazolehydrochloride

To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(1.0 g) in DMF (10 ml) was added 4-chloroquinoline (1.05 g) uner N₂. Thereaction was heated to 140° C. for 2 hours and concentrated in vacuo.The material was filtered washing with CH₂ Cl₂. The material was furtherpurified through recrystallization from MeOH to yield 0.85 g, m.p.266°-267° C.

ANALYSIS: Calculated for C₂₁ H₂₀ N₄ O₂.HCl: 63.55%C 5.33%H 14.12%NFound: 63.54%C 5.17%H 13.98%N

Examples 162-168 are prepared starting from the compound of Example 161and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 1696-Methoxy-3-[1-(4-(7-trifluoromethyl)quinolinyl)piperazinyl]-1,2-benzisoxazolehydrochloride hemihydrate

To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(0.50 g, 2.1 mmol) in DMF (10 ml) was added4-chloro-7-trifluoromethylquinoline (0.75 g, 3.2 mmol) under N₂. Thereaction was heated to 140° C. for 2 hours and concentrated in vacuo.The material was filtered washing with CH₂ Cl₂. The material was furtherpurified through recrystallization from MeOH to yield 0.40 g, m.p.=>250°C.

ANALYSIS: Calculated for C₂₂ H₁₉ N₄ O₂ F₃.HCl.1/2H₂ O: 55.76%C 4.46%H11.82%N Found: 56.19%C 4.00%H 11.86%N

Examples 170-176 are prepared starting from the compound of Example 169and following substantially the procedure set forth in Examples 2-5 and18.

EXAMPLE 1773-[1-(4-(7-Chloro)quinolinyl)piperazinyl]-6-methoxy-1,2-benzisoxazolehydrochloride hemihydrate

To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(0.50 g, 2.1 mmol) in DMF (10 ml) was added 4,7-dichloroquinoline (0.64g, 3.2 mmol)under N₂. The reaction was heated to 140° C. for 2 hours andconcentrated in vacuo. The material was filtered washing with CH₂ Cl₂.The material was further purified through recrystallization from MeOH toyield 0.40 g, m.p.=210°-211 ° C.

ANALYSIS: Calculated for C₂₁ H₁₉ N₄ O₂ Cl.HCl.1/2H₂ O: 57.28%C 4.81%H12.72%N Found: 57.69%C 4.65%H 12.57%N Examples 178-184 are preparedstarting from the compound of Example: 177 and following substantiallythe procedure set forth in Examples 2-5 and 18.

EXAMPLE 185 7-Bromo-6-methxoy-3-(1-piperazinyl)-1,2-benzisoxazolehydrochloride

To a sealed tube was added 7-bromo-3-chloro-6-methoxy-1,2-benzisoxazole(2.0 g) and piperazine (2.6 g). The reaction was heated to 140° C. over30 minutes and then cooled to room temperature. The residue wasdissolved in MeOH and concentrated in vacuo. Flash column chromatography(silica gel) eluting with 30% MeOH/EtOAc provided a residue uponevaporation (1.0 g) which was recrystallized from MeOH/CH₂ Cl₂ /pet.ether to yield 1.0 g, m.p. 268°-269° C.

ANALYSIS: Calculated for C₁₂ H₁₄ N₃ O₂ Br.HCl: 41.34%C 4.34%H 12.05%NFound: 40.79%C 4.23%H 11.84%N

EXAMPLE 1867-Bromo-6-methoxy-3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazole

A stirred solution of 7-bromo-6-methoxy-3-piperazinyl-1,2-benzisoxazolehydrochloride (1.40 g) and 4-chloropyridine hydrochloride (1.01 g) inDMF (30 ml) was heated to 120° C. under N₂ for 4 hours. TLC (silica gel30% MeOH/CH₂ Cl₂) showed no presence of starting material. The solventwas removed in vacuo and the residue was flash chromatographed (silicagel) eluting with 5% MeOH/CH₂ Cl₂ to afford 0.75 g (43%) of the product,m.p. 183°-184° C.

ANALYSIS: Calculated for C₁₇ H₁₇ N₄ O₂ Br: 52.46%C 4.40%H 14.39%N Found:52.35%C 4.28%H 14.37%N

It should be understood that this specification and examples are setforth by way of illustration and not limitation and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention as defined by the appended claims.

We claim:
 1. A compound of the formula ##STR230## wherein X is hydrogen,(C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁ -C₆)alkoxymethyleneoxy, aryl(C₁-C₆)alkoxy, halo, hydroxy, (C₁ -C₆)alkanoylamino, aminocarbonyloxy, (C₁-C₁₀)alkylaminocarbonyloxy, di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁-C₁₀)alkylaminocarbonyloxy, (C₁ -C₆)alkoxycarbonyloxy,tetrahydroisoquinolylcarbonyloxy or aryl(C₁ -C₆)alkylcarbonyloxy;R¹ ishydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonyl,aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl, or di(C₁ -C₆)alkylaminocarbonyl; m is an integerfrom 2 to 7; n is an integer from 0 to 3; andpharmaceutically acceptableacid addition salts thereof and optical and geometric isomers or racemicmixtures thereof.
 2. A pharmaceutically composition which comprises apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of the compound of claim
 1. 3. A method of treating depressionwhich comprises administering to a patient an effective amount of thecompound of claim
 1. 4. The compound of claim 1 whereinX is hydrogen,hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₈)alkylaminocarbonyloxy, tetrahydroisoquinolylcarbonyloxy, di(C₁-C₈)alkylaminocarbonyloxy or aryl(C₁ -C₆)alkylaminocarbonyloxy; R¹ ishydrogen or (C₁ -C₆)alkyl; n is 1 or 2; and m is 2, 3 or
 4. 5. Thecompound of claim 4 whereinX is hydrogen, 5-hydroxy, 5-methoxy,5-methylaminocarbonyloxy, 5-dimethylaminocarbonyloxy,5-methylethylaminocarbonyloxy, 5-bromo, 7-bromo,5-phenylmethylaminocarbonyloxy, 6-chloro, 6-hydroxy, 6-methoxy,6-methylaminocarbonyloxy, 6-methylethylaminocarbonyloxy,6-dimethylaminocarbonyloxy, 6-phenylmethylaminocarbonyloxy,5-hexylaminocarbonyloxy, 5-heptylaminocarbonyloxy,5-tetrahydroisoquinol-2-ylcarbonyloxy, 6-hexylaminocarbonyloxy,6-heptylaminocarbonyloxy or 6-tetrahydroisoquinol-2-ylcarbonyloxy; R¹ ishydrogen, methyl or methylaminocarbonyl; and m is
 2. 6. The compound ofclaim 5 which is6-methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amineand its pharmaceutically acceptable acid addition salts.
 7. The compoundof claim 5 which is3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol and itspharmaceutically acceptable acid addition salts.
 8. The compound ofclaim 5 which is3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ylmethylcarbamate and its pharmaceutically acceptable acid addition salts.9. The compound of claim 5 which is3-[[2-(4-morpholin-yl)ethyl]methylamino]-1,2-benzisoxazo 1-6-ylphenylmethyl carbamate and its pharmaceutically acceptable addition acidsalts.
 10. The compound of claim 5 which is3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-yl1-methylethyl carbamate and its pharmaceutically acceptable acidaddition salts.
 11. The compound of claim 5 which isN-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine and itspharmaceutically acceptable acid addition salts.
 12. The compound ofclaim 5 which is N-[2-(4-morpholinyl)ethyl]1,2-benzisoxazol-3-amine andits pharmaceutically acceptable acid addition salts.
 13. The compound ofclaim 5 which is6-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine and itspharmaceutically acceptable acid addition salts.
 14. The compound ofclaim 5 which is 3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-oland its pharmaceutically acceptable acid addition salts.
 15. Thecompound of claim 5 which is3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-5-ol and itspharmaceutically acceptable acid addition salts.
 16. The compound ofclaim 5 which is 3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ylmethyl carbamate and its pharmaceutically acceptable acid additionsalts.
 17. The compound of claim 5 which is3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-5-yl methylcarbamateand its pharmaceutically acceptable acid addition salts.
 18. Thecompound of claim 5 which is6-chloro-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine and itspharmaceutically acceptable acid addition salts.
 19. The compound ofclaim 5 which is5-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazole-3-amine and itspharmaceutically acceptable acid addition salts.
 20. The compound ofclaim 5 which is7-bromo-6-methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amineand its pharmaceutically acceptable acid addition salts.
 21. Thecompound of claim 5 which is3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-yldimethylcarbamate and its pharmaceutically acceptable acid additionsalts.
 22. The compound of claim 5 which is5-bromo-6-methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amineand its pharmaceutically acceptable acid addition salts.
 23. Thecompound of claim 5 which is3-[[(methylamino)carbonyl][2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ylmethylcarbamate and its pharmaceutically acceptable acid addition salts.24. The compound of claim 5 which is3-[[(methylamino)carbonyl][2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-5-ylmethylcarbamate and its pharmaceutically acceptable acid addition salts.25. The compound of claim 5 which is 7-bromo-3-N-methyl,N-2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-6-ol and itspharmaceutically acceptable acid addition salts.
 26. The compound ofclaim 5 which is 7-bromo-3-[N-methyl,N-2-(4-morpholinyl)ethyl]amino-1,2-benzisoxazol-6-yl dimethylcarbamateand its pharmaceutically acceptable acid addition salts.
 27. A compoundof the formula ##STR231## wherein X is hydrogen, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, (C₁ -C₆)alkoxymethyleneoxy, aryl(C₁ -C₆)alkoxy, halo,hydroxy, (C₁ -C₆)alkanoylamino, aminocarbonyloxy, (C₁-C₁₀)alkylaminocarbonyloxy, di(C₁ -C₁₀)alkylaminocarbonyloxy, aryl(C₁--C₁₀)alkylaminocarbonyloxy, (C₁ -C₆)alkoxycarbonyloxy,tetrahydroisoquinolylcarbonyloxy or aryl(C₁ -C₆)alkylcarbonyloxy;R¹ ishydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonyl,aryloxycarbonyl, aryl(C₁ -C₆)alkoxycarbonyl, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl, or di(C₁ -C₆)alkylaminocarbonyl; m is an integerfrom 2 to 7; n is an integer from 0 to 3; andpharmaceutically acceptableacid addition salts thereof and optical and geometric isomers or racemicmixtures thereof.
 28. The compound of claim 27 whereinX is hydrogen,hydroxy, halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxymethyleneoxy, (C₁ -C₈)alkylaminocarbonyloxy,tetrahydroisoquinolylcarbonyloxy, di(C₁ -C₈)alkylaminocarbonyloxy oraryl(C₁ -C₆)alkylaminocarbonyloxy; R¹ is hydrogen or (C₁ -C₆)alkyl; n is1 or 2; and m is 2, 3 or
 4. 29. The compound of claim 28 whereinX ishydrogen, 5-hydroxy, 5-methoxy, 5-methylaminocarbonyloxy,5-dimethylaminocarbonyloxy, 5-methylethylaminocarbonyloxy, 5-bromo,7-bromo, 6-methoxymethoxy, 5-phenylmethylaminocarbonyloxy, 6-chloro,6-hydroxy, 6-methoxy, 6-methylaminocarbonyloxy,6-methylethylaminocarbonyloxy, 6-dimethylaminocarbonyloxy,6-phenylmethylaminocarbonyloxy, 5-hexylaminocarbonyloxy,5-heptylaminocarbonyloxy, 5-tetrahydroisoquinol-2-ylcarbonyloxy,6-hexylaminocarbonyloxy, 6-heptylaminocarbonyloxy or6-tetrahydroisoquinol-2-ylcarbonyloxy; R¹ is hydrogen or methyl; and mis
 2. 30. The compound of claim 29 which is6-methoxymethoxy-N-[2-(4-thiomorpholinyl)ethyl]-1,2-benzisoxazol-3-amineand its pharmaceutically acceptable acid addition salts.
 31. Thecompound of claim 29 which is3-[[2-(4-thiomorpholinyl)ethyl]amine]-1,2-benzisoxazol-6-ol andpharmaceutically acceptable addition salts.